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  • 1.
    Badhai, Jitendra
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Fröjmark, Anne-Sophie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Davey, Edward J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Ribosomal protein S19 and S24 insufficiency cause distinct cell cycle defects in Diamond-Blackfan anemia2009Ingår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1792, nr 10, s. 1036-1042Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Diamond-Blackfan anemia (DBA) is a severe congenital anemia characterized by a specific decrease of erythroid precursors. The disease is also associated with growth retardation, congenital malformations, a predisposition for malignant disease and heterozygous mutations in either of the ribosomal protein (RP) genes RPS7, RPS17, RPS19, RPS24, RPL5, RPL11 and RPL35a. We show herein that primary fibroblasts from DBA patients with truncating mutations in RPS19 or in RPS24 have a marked reduction in proliferative capacity. Mutant fibroblasts are associated with extended cell cycles and normal levels of p53 when compared to w.t. cells. RPS19 mutant fibroblasts accumulate in the G1 phase, whereas the RPS24 mutant cells show an altered progression in the S phase resulting in reduced levels in the G2/M phase. RPS19 deficient cells exhibit reduced levels of Cyclin-E, CDK2 and retinoblastoma (Rb) protein supporting a cell cycle arrest in the G1 phase. In contrast, RPS24 deficient cells show increased levels of the cell cycle inhibitor p21 and a seemingly opposing increase in Cyclin-E, CDK4 and CDK6. In combination, our results show that RPS19 and RPS24 insufficient fibroblasts have an impaired growth caused by distinct blockages in the cell cycle. We suggest this proliferative constraint to be an important contributing mechanism for the complex extra-hematological features observed in DBA.

  • 2.
    Badhai, Jitendra
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Fröjmark, Anne-Sophie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Razzaghian, Hamid Reza
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Davey, Edward
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Posttranscriptional down-regulation of small ribosomal subunit proteinscorrelates with reduction of 18S rRNA in RPS19 deficiency2009Ingår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 583, nr 12, s. 2049-2053Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ribosomal protein S19 (RPS19) is mutated in patients with Diamond-Blackfan anemia (DBA). We hypothesized that decreased levels of RPS19 lead to a coordinated down-regulation of other ribosomal (r-)proteins at the subunit level. We show that small interfering RNA (siRNA) knock-down of RPS19 results in a relative decrease of small subunit (SSU) r-proteins (S20, S21 and S24) when compared to large subunit (LSU) r-proteins (L3, L9, L30 and L38). This correlates with a relative decrease in 18S rRNA with respect to 28S rRNA. The r-protein mRNA levels remain relatively unchanged indicating a post transcriptional regulation of r-proteins at the level of subunit formation.

  • 3.
    Barrio, Alvaro Martinez
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Centrum för bioinformatik.
    Eriksson, Oskar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Badhai, Jitendra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Fröjmark, Anne-Sophie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Bongcam-Rudloff, Erik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Centrum för bioinformatik.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Targeted Resequencing and Analysis of the Diamond-Blackfan Anemia Disease Locus RPS192009Ingår i: PLoS ONE, ISSN 1932-6203, Vol. 4, nr 7, s. e6172-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The Ribosomal protein S19 gene locus (RPS19) has been linked to two kinds of red cell aplasia, Diamond-Blackfan Anemia (DBA) and Transient Erythroblastopenia in Childhood (TEC). Mutations in RPS19 coding sequences have been found in 25% of DBA patients, but not in TEC patients. It has been suggested that non-coding RPS19 sequence variants contribute to the considerable clinical variability in red cell aplasia. We therefore aimed at identifying non-coding variations associated with DBA or TEC phenotypes. METHODOLOGY/PRINCIPAL FINDINGS: We targeted a region of 19'980 bp encompassing the RPS19 gene in a cohort of 89 DBA and TEC patients for resequencing. We provide here a catalog of the considerable, previously unrecognized degree of variation in this region. We identified 73 variations (65 SNPs, 8 indels) that all are located outside of the RPS19 open reading frame, and of which 67.1% are classified as novel. We hypothesize that specific alleles in non-coding regions of RPS19 could alter the binding of regulatory proteins or transcription factors. Therefore, we carried out an extensive analysis to identify transcription factor binding sites (TFBS). A series of putative interaction sites coincide with detected variants. Sixteen of the corresponding transcription factors are of particular interest, as they are housekeeping genes or show a direct link to hematopoiesis, tumorigenesis or leukemia (e.g. GATA-1/2, PU.1, MZF-1). CONCLUSIONS: Specific alleles at predicted TFBSs may alter the expression of RPS19, modify an important interaction between transcription factors with overlapping TFBS or remove an important stimulus for hematopoiesis. We suggest that the detected interactions are of importance for hematopoiesis and could provide new insights into individual response to treatment.

  • 4.
    Dahlqvist, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Klar, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Tiwari, Neha
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Törmä, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Badhai, Jitendra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Pujol, Ramon
    van Steensel, Maurice A. M.
    Brinkhuizen, Tjinta
    Gijezen, Lieke
    Chaves, Antonio
    Tadini, Gianluca
    Vahlquist, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis2010Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 86, nr 4, s. 596-603Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    KLICK syndrome is a rare autosomal-recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic papules, and ichthyosiform scaling. In order to establish the genetic cause of this disorder, we collected DNA samples from eight European probands. Using high-density genome-wide SNP analysis, we identified a 1.5 Mb homozygous candidate region on chromosome 13q. Sequence analysis of the ten annotated genes in the candidate region revealed homozygosity for a single-nucleotide deletion at position c.-95 in the proteasome maturation protein (POMP) gene, in all probands. The deletion is included in POMP transcript variants with long 5' untranslated regions (UTRs) and was associated with a marked increase of these transcript variants in keratinocytes from KLICK patients. POMP is a ubiquitously expressed protein and functions as a chaperone for proteasome maturation. Immunohistochemical analysis of skin biopsies from KLICK patients revealed an altered epidermal distribution of POMP, the proteasome subunit proteins alpha 7 and beta 5, and the ER stress marker CHOP. Our results suggest that KLICK syndrome is caused by a single-nucleotide deletion in the 5' UTR of POMP resulting in altered distribution of POMP in epidermis and a perturbed formation of the outermost layers of the skin. These findings imply that the proteasome has a prominent role in the terminal differentiation of human epidermis.

  • 5.
    Fröjmark, Anne-Sophie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Badhai, Jitendra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Klar, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Thuveson, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Cooperative effect of ribosomal protein s19 and Pim-1 kinase on murine c-Myc expression and myeloid/erythroid cellularity2010Ingår i: Journal of Molecular Medicine, ISSN 0946-2716, E-ISSN 1432-1440, Vol. 88, nr 1, s. 39-46Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Diamond Blackfan anemia (DBA) is a bone marrow failure syndrome associated with heterozygous mutations in the ribosomal protein S19 (RPS19) gene in a subgroup of patients. One of the interacting partners with RPS19 is the oncoprotein PIM-1 kinase. We intercrossed Rps19+/- and Pim-1-/- mice strains to study the effect from the disruption of both genes. The double mutant (Rps19+/-Pim-1-/-) mice display normal growth with increased peripheral white- and red blood cell counts when compared to the w.t. mice (Rps19+/+Pim-1+/+). Molecular analysis of bone marrow cells in Rps19+/-Pim-1-/- mice revealed up-regulated levels of c-Myc and the anti-apoptotic factors Bcl2, BclXL and Mcl-1. This is associated with a reduction of the apoptotic factors Bak and Caspase 3 as well as the cell cycle regulator p21. Our findings suggest that combined Rps19 insufficiency and Pim-1 deficiency promote murine myeloid cell growth through a deregulation of c-Myc and a simultaneous up-regulation of anti-apoptotic Bcl proteins.

  • 6.
    Fröjmark, Anne-Sophie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sobol, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Entesarian, Miriam
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kilander, Michaela B C
    Gabrikova, Dana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nawaz, Sadia
    Baig, Shahid M
    Schulte, Gunnar
    Klar, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mutations in frizzled 6 cause isolated autosomal-recessive nail dysplasia2011Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 88, nr 6, s. 852-860Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Inherited and isolated nail malformations are rare and heterogeneous conditions. We identified two consanguineous pedigrees in which some family members were affected by isolated nail dysplasia that suggested an autosomal-recessive inheritance pattern and was characterized by claw-shaped nails, onychauxis, and onycholysis. Genome-wide SNP array analysis of affected individuals from both families showed an overlapping and homozygous region of 800 kb on the long arm of chromosome 8. The candidate region spans eight genes, and DNA sequence analysis revealed homozygous nonsense and missense mutations in FZD(6), the gene encoding Frizzled 6. FZD(6) belongs to a family of highly conserved membrane-bound WNT receptors involved in developmental processes and differentiation through several signaling pathways. We expressed the FZD(6) missense mutation and observed a quantitative shift in subcellular distribution from the plasma membrane to the lysosomes, where the receptor is inaccessible for signaling and presumably degraded. Analysis of human fibroblasts homozygous for the nonsense mutation showed an aberrant response to both WNT-3A and WNT-5A stimulation; this response was consistent with an effect on both canonical and noncanonical WNT-FZD signaling. A detailed analysis of the Fzd(6)(-/-) mice, previously shown to have an altered hair pattern, showed malformed claws predominantly of the hind limbs. Furthermore, a transient Fdz6 mRNA expression was observed in the epidermis of the digital tips at embryonic day 16.5 during early claw morphogenesis. Thus, our combined results show that FZD6 mutations can result in severe defects in nail and claw formation through reduced or abolished membranous FZD(6) levels and several nonfunctional WNT-FZD pathways.

  • 7.
    Kele, Malin
    et al.
    Karolinska Inst, Dept Neurosci, Retziusvag 8, S-17177 Stockholm, Sweden..
    Day, Kelly
    Karolinska Inst, Dept Neurosci, Retziusvag 8, S-17177 Stockholm, Sweden..
    Ronnholm, Harriet
    Karolinska Inst, Dept Neurosci, Retziusvag 8, S-17177 Stockholm, Sweden..
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Falk, Anna
    Karolinska Inst, Dept Neurosci, Retziusvag 8, S-17177 Stockholm, Sweden..
    Generation of human iPS cell line CTL07-II from human fibroblasts, under defined and xeno-free conditions2016Ingår i: Stem Cell Research, ISSN 1873-5061, E-ISSN 1876-7753, Vol. 17, nr 3, s. 474-478Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    CTL07-II is a healthy feeder-free and characterized human induced pluripotent stem (iPS) cell line. Cultured under xeno-free and defined conditions. The line is generated from healthy human fibroblasts with non-integrating Sendai virus vectors encoding the four Yamanaka factors, OCT4, SOX2, KLF4 and cMYC. The generated iPS cells are free from reprogramming vectors and their purity, karyotypic stability and pluripotent capacity is confirmed.

  • 8. Kilander, Michaela B. C.
    et al.
    Petersen, Julian
    Andressen, Kjetil Wessel
    Ganji, Ranjani Sri
    Levy, Finn Olav
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bryja, Vitezslav
    Schulte, Gunnar
    Disheveled regulates precoupling of heterotrimeric G proteins to Frizzled 62014Ingår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, nr 5, s. 2293-2305Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Frizzleds (FZDs) are classified as G-protein-coupling receptors, but how signals are initiated and specified through heterotrimeric G proteins is unknown. FZD(6) regulates convergent extension movements, and its C-terminal Arg511Cys mutation causes nail dysplasia in humans. We investigated the functional relationship between FZD(6), Disheveled (DVL), and heterotrimeric G proteins. Live cell imaging combined with fluorescence recovery after photobleaching (FRAP) revealed that inactive human FZD(6) precouples to G(i1) and G(q) but not to G(oA),G(s), and G(12) proteins. G-protein coupling is measured as a 10-20% reduction in the mobile fraction of fluorescently tagged G proteins on chemical receptor surface cross-linking. The FZD(6) Arg511Cys mutation is incapable of G-protein precoupling, even though it still binds DVL. Using both FRAP and Forster resonance energy transfer (FRET) technology, we showed that the FZD(6)-G(i1) and FZD-G(q) complexes dissociate on WNT-5A stimulation. Most important, G-protein precoupling of FZD(6) and WNT-5A-induced signaling to extracellular signal-regulated kinase1/2 were impaired by DVL knockdown or overexpression, arguing for a strict dependence of FZD(6)-G-protein coupling on DVL levels and identifying DVL as a master regulator of FZD/G-protein signaling. In summary, we propose a mechanistic connection between DVL and G proteins integrating WNT, FZD, G-protein, and DVL function.Kilander, M. B. C., Petersen, J., Andressen, K. W., Ganji, R. S. Levy, F. O., Schuster, J., Dahl N., Bryja, V., Schulte, G. Disheveled regulates precoupling of heterotrimeric G proteins to Frizzled 6.

  • 9.
    Klar, Joakim
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Piontek, Jörg
    Milatz, Susanne
    Tariq, Muhammad
    Jameel, Muhammad
    Breiderhoff, Tilman
    Schuster, Jens
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Fatima, Ambrin
    Asif, Maria
    Sher, Muhammad
    Mäbert, Katrin
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Fromm, Anja
    Baig, Shahid M
    Günzel, Dorothee
    Dahl, Niklas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Altered paracellular cation permeability due to a rare CLDN10B variant causes anhidrosis and kidney damage2017Ingår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, nr 7, artikel-id e1006897Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Claudins constitute the major component of tight junctions and regulate paracellular permeability of epithelia. Claudin-10 occurs in two major isoforms that form paracellular channels with ion selectivity. We report on two families segregating an autosomal recessive disorder characterized by generalized anhidrosis, severe heat intolerance and mild kidney failure. All affected individuals carry a rare homozygous missense mutation c.144C>G, p.(N48K) specific for the claudin-10b isoform. Immunostaining of sweat glands from patients suggested that the disease is associated with reduced levels of claudin-10b in the plasma membranes and in canaliculi of the secretory portion. Expression of claudin-10b N48K in a 3D cell model of sweat secretion indicated perturbed paracellular Na+ transport. Analysis of paracellular permeability revealed that claudin-10b N48K maintained cation over anion selectivity but with a reduced general ion conductance. Furthermore, freeze fracture electron microscopy showed that claudin-10b N48K was associated with impaired tight junction strand formation and altered cis-oligomer formation. These data suggest that claudin-10b N48K causes anhidrosis and our findings are consistent with a combined effect from perturbed TJ function and increased degradation of claudin-10b N48K in the sweat glands. Furthermore, affected individuals present with Mg2+ retention, secondary hyperparathyroidism and mild kidney failure that suggest a disturbed reabsorption of cations in the kidneys. These renal-derived features recapitulate several phenotypic aspects detected in mice with kidney specific loss of both claudin-10 isoforms. Our study adds to the spectrum of phenotypes caused by tight junction proteins and demonstrates a pivotal role for claudin-10b in maintaining paracellular Na+ permeability for sweat production and kidney function.

  • 10.
    Klar, Joakim
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Khan, Tahir Naeem
    Jameel, Muhammad
    Mäbert, Katrin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Forsberg, Lars A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Baig, Shehla Anjum
    Baig, Shahid Mahmood
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Whole exome sequencing identifies LRP1 as a pathogenic gene in autosomal recessive keratosis pilaris atrophicans2015Ingår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 52, nr 9, s. 599-606Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Keratosis pilaris atrophicans (KPA) is a group of rare genodermatoses characterised by perifollicular keratosis and inflammation that progresses to atrophy and scars of the facial skin. Keratosis pilaris of extensor areas of limbs is a common associated finding. Most cases with KPA are sporadic and no consistent inheritance pattern has been documented.

    Methods A large consanguineous Pakistani pedigree segregating autosomal recessive KPA of a mixed type was subject to autozygosity mapping and whole exome sequencing. Quantification of mRNA and protein levels was performed on fibroblasts from affected individuals. Cellular uptake of the low-density lipoprotein (LDL) receptor-related protein 1 (LRP1) ligand alpha 2-macroglobulin (alpha M-2) was quantified using fluorescence confocal microscopy.

    Results Genetic analyses identified a unique homozygous missense variant (K1245R) in the LRP1 in all affected family members. LRP1 encodes the LRP1, a multifunctional cell surface receptor with endocytic functions that belongs to the LDL receptor family. The LRP1 mRNA and LRP1 protein levels in fibroblasts of affected individuals were markedly reduced when compared with controls. Similarly, the LRP1-mediated cellular uptake of alpha M-2 was reduced in patient fibroblasts.

    Conclusions This is the first report on LRP1 as a pathogenic gene for autosomal recessive KPA and keratosis pilaris. The inflammatory characteristics of the KPA entity in our family suggest a link to the immune-regulatory functions of LRP1.

  • 11.
    Kyriakopoulou, Christina
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Larsson, Pontus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Liu, Lei
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Schuster, Jens
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Söderbom, Fredrik
    Kirsebom, Leif A.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Virtanen, Anders
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    U1-like snRNAs lacking complementarity to canonical 5' splice sites2006Ingår i: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 12, nr 9, s. 1603-1611Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have detected a surprising heterogeneity among human spliceosomal U1 small nuclear RNA (snRNA). Most interestingly, we have identified three U1 snRNA variants that lack complementarity to the canonical 5' splice site (5'SS) GU dinucleotide. Furthermore, we have observed heterogeneity among the identified variant U1 snRNA genes caused by single nucleotide polymorphism (SNP). The identified snRNAs were ubiquitously expressed in a variety of human tissues representing different stages of development and displayed features of functional spliceosomal snRNAs, i.e., trimethylated cap structures, association with Sm proteins and presence in nuclear RNA-protein complexes. The unanticipated heterogeneity among spliceosomal snRNAs could contribute to the complexity of vertebrates by expanding the coding capacity of their genomes.

  • 12. Lizano, Esther
    et al.
    Schuster, Jens
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Mueller, Martin
    Kelso, Janet
    Mörl, Mario
    A splice variant of the human CCA-adding enzyme with modified activity2007Ingår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 366, nr 4, s. 1258-1265Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The human CCA-adding enzyme (tRNA nucleotidyltransferase) is an essential enzyme that catalyzes the addition of the CCA terminus to the 3′ end of tRNA precursors, a reaction which is a fundamental prerequisite for mature tRNAs to become aminoacylated and to participate in protein biosynthesis. To date only one form of this enzyme has been identified in humans. Here, we describe the sequence and activity of a splice variant of the human CCA-adding enzyme identified in public cDNA databases. The in silico analyses performed on this splice variant indicate that there is conservation of the alternative splice donor site among species and indicate that it seems to be used in vivo. Moreover, the recombinantly expressed protein is active in vitro and accepts tRNA transcripts as substrates incorporating the dinucleotide sequence CC to their 3′ end, in contrast to the activity of the full length enzyme. These findings strongly suggest that the splice variant of the human CCA-adding enzyme is expressed in the cell although the in vivo function remains unclear.

  • 13.
    Mansouri, Mahmoud Reza
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Badhai, Jitendra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Stattin, Eva-Lena
    Lösel, Ralf
    Wehling, Martin
    Carlsson, Birgit
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Hovatta, Outi
    Karlström, Per Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Golovleva, Irina
    Toniolo, Daniela
    Bione, Silvia
    Peluso, John
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Alterations in the expression, structure and function of progesterone receptor membrane component-1 (PGRMC1) in premature ovarian failure2008Ingår i: Human molecular genetics, ISSN 1460-2083, Vol. 17, nr 23, s. 3776-83Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Premature ovarian failure (POF) is characterized by hypergonadotropic hypogonadism and amenorrhea before the age of 40. The condition has a heterogeneous background but genetic factors are demonstrated by the occurrence of familial cases. We identified a mother and daughter with POF both of whom carry an X;autosome translocation [t(X;11)(q24;q13)]. RNA expression studies of genes flanking the X-chromosome breakpoint revealed that both patients have reduced expression levels of the gene Progesterone Receptor Membrane Component-1 (PGRMC1). Mutation screening of 67 females with idiopathic POF identified a third patient with a missense mutation (H165R) located in the cytochrome b5 domain of PGRMC1. PGRMC1 mediates the anti-apoptotic action of progesterone in ovarian cells and it acts as a positive regulator of several cytochrome P450 (CYP)-catalyzed reactions. The CYPs are critical for intracellular sterol metabolism, including biosynthesis of steroid hormones. We show that the H165R mutation associated with POF abolishes the binding of cytochrome P450 7A1 (CYP7A1) to PGRMC1. In addition, the missense mutation attenuates PGRMC1's ability to mediate the anti-apoptotic action of progesterone in ovarian cells. These findings suggest that mutant or reduced levels of PGMRC1 may cause POF through impaired activation of the microsomal cytochrome P450 and increased apoptosis of ovarian cells.

  • 14.
    Pijuan-Galito, Sara
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Tamm, Christoffer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sobol, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Forsberg, Lars A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Merry, Catherine L. R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Univ Nottingham, Wolfson Ctr Stem Cells, Stem Cell Glycobiol Grp, Tissue Engn & Modelling Room A59, Nottingham NG7 2RD, England.
    Annerén, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. GE Healthcare Biosci AB, Bjorkgatan 30, S-75184 Uppsala, Sweden.
    Human serum-derived protein removes the need for coating in defined human pluripotent stem cell culture2016Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, artikel-id 12170Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Reliable, scalable and time-efficient culture methods are required to fully realize the clinical and industrial applications of human pluripotent stem (hPS) cells. Here we present a completely defined, xeno-free medium that supports long-term propagation of hPS cells on uncoated tissue culture plastic. The medium consists of the Essential 8 (E8) formulation supplemented with inter-alpha-inhibitor (I alpha I), a human serum-derived protein, recently demonstrated to activate key pluripotency pathways in mouse PS cells. IaI efficiently induces attachment and long-term growth of both embryonic and induced hPS cell lines when added as a soluble protein to the medium at seeding. IaI supplementation efficiently supports adaptation of feeder-dependent hPS cells to xeno-free conditions, clonal growth as well as single-cell survival in the absence of Rho-associated kinase inhibitor (ROCKi). This time-efficient and simplified culture method paves the way for large-scale, high-throughput hPS cell culture, and will be valuable for both basic research and commercial applications.

  • 15. Rasool, Mahmood
    et al.
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Aslam, Muhammad
    Tariq, Muhammad
    Ahmad, Ilyas
    Ali, Amjad
    Entesarian, Miriam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Baig, Shahid Mahmood
    A novel missense mutation in the EDA gene associated with X-linked recessive isolated hypodontia2008Ingår i: Journal of Human Genetics, ISSN 1434-5161, E-ISSN 1435-232X, Vol. 53, nr 10, s. 894-8Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Isolated hypodontia, or congenital absence of one to six permanent teeth (OMIM 300606), is a common condition that affects about 20% of individuals worldwide. We identified two extended Pakistani pedigrees segregating X-linked hypodontia with variable expressivity. Affected males show no other associated anomalies, and obligate carrier females have normal dentition. We analyzed the families with polymorphic markers in the ectodysplasin A (EDA) gene region and obtained significant linkage to the phenotype in each pedigree (Z(max) 3.29 and 2.65, respectively, at theta = 0.00). Sequence analysis of the coding regions of EDA revealed a novel missense mutation c.1091T>C resulting in a methionine to threonine substitution (p.M364T) in the tumor necrosis factor (TNF) homology domain. Met364 is a highly conserved residue located on the outer surface of the EDA protein. From our findings, we suggest that the mutation disturbs but does not destroy the EDA structure, resulting in the partial and unusually mild ED phenotype restricted to hypodontia.

  • 16.
    Schuster, Jens
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Betat, Heike
    Mörl, Mario
    Is yeast on its way to evolving tRNA editing?2005Ingår i: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 6, nr 4, s. 367-372Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In human mitochondria, genes for tRNA(Tyr) and tRNA(Cys) overlap by a single nucleotide. From polycistronic precursors, a 3'-truncated upstream tRNA(Tyr) is released, missing the overlapping position. A subsequent editing reaction restores this position. Similar mitochondrial tRNA gene overlaps exist in all metazoans, but not in organisms such as yeast or Escherichia coli. Therefore, we asked whether tRNA overlaps are processed in these organisms. Corresponding constructs were introduced and transcripts tested for processing and editing in E. coli and yeast. E. coli produces only one functional tRNA from these precursors, indicating that tRNA overlaps are incompatible with its processing pathway. In contrast, yeast processes overlapping tRNAs similar to human mitochondria, releasing a 3'-truncated upstream tRNA. This tRNA is restored in an editing-like event, although yeast does not carry a corresponding endogenous editing substrate. These findings support the hypothesis of the evolution of editing by recruitment of a pre-existing and promiscuous editing enzyme.

  • 17.
    Schuster, Jens
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Fröjmark, Anne-Sophie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Nilsson, Per
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Badhai, Jitendra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Virtanen, Anders
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Ribosomal protein S19 binds to its own mRNA with reduced affinity in Diamond-Blackfan anemia2010Ingår i: Blood Cells, Molecules & Diseases, ISSN 1079-9796, E-ISSN 1096-0961, Vol. 45, nr 1, s. 23-28Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Heterozygous mutations in the ribosomal protein S19 (RPS19) gene are associated with Diamond-Blackfan anemia (DBA). The mechanism by which RPS19 mediates anemia are still unclear, as well as the regulation of RPS19 expression. We show herein that RPS19 binds specifically to the 5' untranslated region of its own mRNA with an equilibrium binding constant (K(D)) of 4.1+/-1.9 nM. We investigated the mRNA binding properties of two mutant RPS19 proteins (W52R and R62W) identified in DBA patients. We observed a significant increase in K(D) for both proteins (16.1+/-2.1 and 14.5+/-4.9 nM, respectively), indicating a reduced RNA binding capability (p<0.05). We suggest that the binding of RPS19 to its mRNA has a regulatory function and hypothesize that the weaker RNA binding of mutant rRPS19 may have implications for the pathophysiological mechanisms in DBA.

  • 18.
    Schuster, Jens
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Halvardson, Jonatan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Lorenzo, Laureanne Pilar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Ameur, Adam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Sobol, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Raykova, Doroteya
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Annerén, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Feuk, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Transcriptome Profiling Reveals Degree of Variability in Induced Pluripotent Stem Cell Lines: Impact for Human Disease Modeling2015Ingår i: Cellular Reprogramming, ISSN 2152-4971, E-ISSN 2152-4998, Vol. 17, nr 5, s. 327-337Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Induced pluripotent stem cell (iPSC) technology has become an important tool for disease modeling. Insufficient data on the variability among iPSC lines derived from a single somatic parental cell line have in practice led to generation and analysis of several, usually three, iPSC sister lines from each parental cell line. We established iPSC lines from a human fibroblast line (HDF-K1) and used transcriptome sequencing to investigate the variation among three sister lines (iPSC-K1A, B, and C). For comparison, we analyzed the transcriptome of an iPSC line (iPSC-K5B) derived from a different fibroblast line (HDF-K5), a human embryonic stem cell (ESC) line (ESC-HS181), as well as the two parental fibroblast lines. All iPSC lines fulfilled stringent criteria for pluripotency. In an unbiased cluster analysis, all stem cell lines (four iPSCs and one ESC) clustered together as opposed to the parental fibroblasts. The transcriptome profiles of the three iPSC sister lines were indistinguishable from each other, and functional pathway analysis did not reveal any significant hits. In contrast, the expression profiles of the ESC line and the iPSC-K5B line were distinct from that of the sister lines iPSC-K1A, B, and C. Differentiation to embryoid bodies and subsequent analysis of germ layer markers in the five stem cell clones confirmed that the distribution of their expression profiles was retained. Taken together, our observations stress the importance of using iPSCs of different parental origin rather than several sister iPSC lines to distinguish disease-associated mechanisms from genetic background effects in disease modeling.

  • 19.
    Schuster, Jens
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Karlsson, Teresia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Karlström, Per-Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Poromaa, Inger Sundström
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Down-regulation of progesterone receptor membrane component 1 (PGRMC1) in peripheral nucleated blood cells associated with premature ovarian failure (POF) and polycystic ovary syndrome (PCOS)2010Ingår i: Reproductive Biology and Endocrinology, ISSN 1477-7827, E-ISSN 1477-7827, Vol. 8, s. 58-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Progesterone receptor membrane component 1 (PGRMC1) is a member of a progesterone-binding complex implicated in female reproduction. We aimed i) to determine the natural expression of PGRMC1 in peripheral nucleated blood cells throughout the menstrual cycle and ii) to investigate any association between PGRMC1 levels in leukocytes and conditions characterized by reduced fertility. METHODS: We analyzed PGRMC1 expression in peripheral leukocytes from 15 healthy cycling women over four weeks. Additionally, we determined PGRMC1 levels in samples from patients with premature ovarian failure (POF) and polycystic ovary syndrome (PCOS) as well as in healthy postmenopausal women and male controls. The levels of PGRMC1 protein in nucleated peripheral blood cells were quantified by Western blot analysis. RESULTS: PGRMC1 levels did not vary significantly throughout the menstrual cycle. We observed a significant down-regulation of PGRMC1 in postmenopausal women and in patients with premature ovarian failure (POF) and polycystic ovary syndrome (PCOS) when compared to early follicular phase of healthy women. CONCLUSION: This study suggests that reduced levels of PGRMC1 in peripheral leukocytes are associated with perturbed ovulatory function.

  • 20.
    Schuster, Jens
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Khan, Tahir Naeem
    Tariq, Muhammad
    Shaiq, Pakeeza Arzoo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Mäbert, Katrin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Baig, Shahid Mahmood
    Klar, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala University.
    Exome sequencing circumvents missing clinical data and identifies a BSCL2 mutation in congenital lipodystrophy2014Ingår i: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 15, artikel-id 71Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Exome sequencing has become more and more affordable and the technique has emerged as an important diagnostic tool for monogenic disorders at early stages of investigations, in particular when clinical information is limited or unspecific as well as in cases of genetic heterogeneity.

    METHODS: We identified a consanguineous Pakistani family segregating an autosomal recessive phenotype characterized by muscular hypertrophy, mild mental retardation and skeletal abnormalities. The available clinical information was incomplete and we applied whole exome sequencing in an affected family member for the identification of candidate gene variants.

    RESULTS: Exome sequencing identified a previously unreported homozygous mutation in the acceptor splice site of intron 5 in the BSCL2 gene (c.574-2A > G). Expression analysis revealed that the mutation was associated with skipping of exon 6. BSCL2 mutations are associated with Berardinelli-Seip congenital lipodystrophy and a clinical re-evaluation of affected individuals confirmed the diagnosis.

    CONCLUSIONS: Exome sequencing is a powerful technique for the identification of candidate gene variants in Mendelian traits. We applied this technique on a single individual affected by a likely autosomal recessive disorder without access to complete clinical details. A homozygous and truncating mutation was identified in the BSCL2 gene suggesting congenital generalized lipodystrophy. Incomplete phenotypic delineations are frequent limiting factors in search for a diagnosis and may lead to inappropriate care and follow-up. Our study exemplifies exome sequencing as a powerful diagnostic tool in Mendelian disorders that may complement missing clinical information and accelerate clinical diagnosis.

  • 21.
    Schuster, Jens
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sundblom, Jimmy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Thuresson, Ann-Charlotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hassin-Baer, Sharon
    Klopstock, Thomas
    Dichgans, Martin
    Cohen, Oren S.
    Raininko, Raili
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Melberg, Atle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms2011Ingår i: Neurogenetics, ISSN 1364-6745, E-ISSN 1364-6753, Vol. 12, nr 1, s. 65-72Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms features micturition urgency, constipation, erectile dysfunction, and orthostatic hypotension, usually followed by pyramidal signs and ataxia. Peripheral nerve conduction is normal. The disease is often mistaken for multiple sclerosis in the initial phase. There is a characteristic pattern of white matter changes in the brain and spinal cord on magnetic resonance imaging (MRI), mild atrophy of the brain, and a more marked atrophy of the spinal cord. ADLD is associated with duplications of the lamin B1 (LMNB1) gene but the mechanism by which the rearrangement conveys the phenotype is not fully defined. We analyzed four unrelated families segregating ADLD with autonomic symptoms for duplications of the LMNB1 gene. A single nucleotide polymorphism (SNP) array analysis revealed novel duplications spanning the entire LMNB1 gene in probands from each of the four families. We then analyzed the expression of lamin B1 in peripheral leukocytes by Western blot analysis in five patients from two available families. The protein levels of lamin B1 were found significantly increased. These results indicate that the ADLD phenotype associated with LMNB1 duplications is mediated by increased levels of the lamin B1 protein. Furthermore, we show that a molecular diagnosis for ADLD with autonomic symptoms can be obtained by a direct analysis of lamin B1 in peripheral leukocytes.

  • 22. Schürer, Heike
    et al.
    Lang, Kathrin
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Mörl, Mario
    A universal method to produce in vitro transcripts with homogeneous 3' ends2002Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 30, nr 12, s. e56-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A method is described that allows a general drawback of in vitro transcription assays to be overcome: RNA polymerases tend to add extra nucleotides to the RNA 3' end that are not encoded in the linearized DNA template. Furthermore, these polymerases show a considerable rate of premature termination close to the RNA's 3' end. These features lead to a decreased yield of full-length transcripts and often make it difficult to determine and isolate the correctly transcribed full-length RNA. The hammerhead ribozyme is frequently used in cis to cleave off these extra nucleotides. However, the upstream sequence requirements of this ribozyme restrict its general usability. In contrast, the hepatitis delta virus ribozyme has no such requirements and can therefore be applied to any RNA sequence in cis. Due to the catalytic activity of the ribozyme, the desired transcript is released as an RNA molecule with a homogeneous 3' end. The resulting 2',3'-cyclo-phosphate group of the released RNA can be easily and efficiently removed by T4 polynucleotide kinase treatment. The presented method can be applied for virtually any sequence to be transcribed and is therefore superior to other ribozyme strategies, suggesting possible applications in every field where transcripts with homogeneous 3' ends are required.

  • 23. Shahsavani, M
    et al.
    Pronk, R J
    Falk, R
    Lam, M
    Moslem, M
    Linker, S B
    Salma, J
    Day, K
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Anderlid, B-M
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Gage, F H
    Falk, A
    An in vitro model of lissencephaly: expanding the role of DCX during neurogenesis.2017Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lissencephaly comprises a spectrum of brain malformations due to impaired neuronal migration in the developing cerebral cortex. Classical lissencephaly is characterized by smooth cerebral surface and cortical thickening that result in seizures, severe neurological impairment and developmental delay. Mutations in the X-chromosomal gene DCX, encoding doublecortin, is the main cause of classical lissencephaly. Much of our knowledge about DCX-associated lissencephaly comes from post-mortem analyses of patient's brains, mainly since animal models with DCX mutations do not mimic the disease. In the absence of relevant animal models and patient brain specimens, we took advantage of induced pluripotent stem cell (iPSC) technology to model the disease. We established human iPSCs from two males with mutated DCX and classical lissencephaly including smooth brain and abnormal cortical morphology. The disease was recapitulated by differentiation of iPSC into neural cells followed by expression profiling and dissection of DCX-associated functions. Here we show that neural stem cells, with absent or reduced DCX protein expression, exhibit impaired migration, delayed differentiation and deficient neurite formation. Hence, the patient-derived iPSCs and neural stem cells provide a system to further unravel the functions of DCX in normal development and disease.Molecular Psychiatry advance online publication, 19 September 2017; doi:10.1038/mp.2017.175.

  • 24.
    Sobol, Maria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Raykova, Doroteya
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Cavelier, Lucia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Khalfallah, Ayda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Methods of Reprogramming to Induced Pluripotent Stem Cell Associated with Chromosomal Integrity and Delineation of a Chromosome 5q Candidate Region for Growth Advantage2015Ingår i: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 24, nr 17, s. 2032-2040Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Induced pluripotent stem cells (iPSCs) have brought great promises for disease modeling and cell-based therapies. One concern related to the use of reprogrammed somatic cells is the loss of genomic integrity and chromosome stability, a hallmark for cancer and many other human disorders. We investigated 16 human iPSC lines reprogrammed by nonintegrative Sendai virus (SeV) and another 16 iPSC lines generated by integrative lentivirus for genetic changes. At early passages we detected cytogenetic rearrangements in 44% (7/16) of iPSC lines generated by lentiviral integration whereas the corresponding figure was 6% (1/16) using SeV-based delivery. The rearrangements were numerical and/or structural with chromosomes 5 and 12 as the most frequently involved chromosomes. Three iPSC lines with chromosome 5 aberrations were derived from one and the same donor. We present in this study the aberrant karyotypes including a duplication of chromosome 5q13q33 that restricts a candidate region for growth advantage. Our results suggest that the use of integrative lentivirus confers a higher risk for cytogenetic abnormalities at early passages when compared to SeV-based reprogramming. In combination, our findings expand the knowledge on acquired cytogenetic aberrations in iPSC after reprogramming and during culture.

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